The broad long-term objective of this proposal is to enhance our understanding of the transcriptional mechanisms regulating leukemogenesis. In up to 30% of B-ALL patients, t(12;21) creates a fusion product, TEL/AML-1B, which converts AML-1B from an activator to repressor of transcription. In the majority of these cases, the non-translocated TEL allele is deleted. Therefore, we hypothesize that TEL plays a key role in regulating transcription and leukemogenesis. The specific aims are to determine the mechanisms of TEL/AML-1B- mediated repression of basal and AML-1B-induced transcription and to investigate whether TEL is a tumor suppressor. To determine the mechanism of transcriptional repression by TEL/AML-1B, we will make point mutations within the TEL-encoded helix- loop-helix domain and define the region required for transcriptional repression and protein-protein interactions. We will also design promoter constructs that will allow us to determine whether TEL/AML-1B is short- or long-range repressor. Secondly, we will create conditional TEL knock-out mice using the Cre-loxP recombination system. We will also cross TEL- deficient mice with TEL/AML-1B transgenic mice to re-create the genotype seen in B-ALL patients. These mice will be analyzed the development of tumors. The data obtained from these studies will enhance our understanding of the roles of TEL in transcriptional regulation and leukemogenesis.